Fast dissolving orally consumable films

ABSTRACT

Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-forming polymer such as pullulan. Edible films are disclosed that include pullulan and antimicrobially effective amounts of the essential oils thymol, methyl salicylate, eucalyptol and menthol. The edible films are effective at killing the plaque-producing germs that cause dental plaque, gingivitis and bad breath. The film can also contain pharmaceutically active agents. Methods for producing the films are also disclosed.

This Application is a continuation of application Ser. No. 09/836,474,filed on Apr. 18, 2001, now U.S. Pat. No. 7,025,983, which is adivisional of patent application Ser. No. 09/395,104, filed on Sep. 14,1999, now U.S. Pat. No. 6,596,298 which claims the benefit ofprovisional patent application No. 60/101,798, filed Sep. 25, 1998.

FIELD OF THE INVENTION

This invention relates to fast dissolving orally consumable films. Thefilms are used to deliver breath deodorizing agents, antimicrobialagents and salivary stimulants to the oral cavity. The films can also beused to deliver pharmaceutically active agents.

BACKGROUND OF THE INVENTION

In a more perfect world, people would thoroughly cleanse their mouthsafter each meal as part of their routine oral hygienic practices.Unfortunately, several factors conspire to prevent widespread compliancewith this basic requirement of a good oral cleaning regimen.

Oral cleansing can be difficult or inconvenient at times, depending onthe nature of the cleansing and the situation in which the cleansingmust occur. Brushing, flossing, cleaning your tongue and gargling usinga variety of devices and compositions well-suited for the privacy ofone's home are common oral care practices. However, the devices andcompositions used in oral cleansing practices are less convenient to useaway from home, where bathroom facilities might be scarce, unavailableor unsanitary.

As brushing, flossing, cleaning your tongue and gargling in public arenot considered to be socially acceptable behaviors in many, if not allcultures, a variety of less obtrusive oral cleansing products have beendeveloped. These include breath-freshening gums and lozenges. Althoughgums and lozenges have been formulated to achieve a variety ofbeneficial effects, they are not always socially acceptable. Forexample, gum is expressly banned from certain institutions, such asschools as well as in certain countries, such as Singapore. Gums andmints are used over extended periods of time, and they require an amountof sucking or chewing action on the part of the consumer, which can bedistracting; tedious and undesirable.

Another portable oral cleansing product is a mouthspray. Like amouthwash, a mouthspray can provide the consumer with a quick burst ofstrong breath-freshening action, which might be overwhelming in anextended-consumption product like gum or lozenges. On the other hand,mouthsprays are obtrusive. Spraying a mouthspray typically generates anoise, which undesirably draws the attention of the public to theconsumer. Moreover, mouthsprays are typically packaged in relativelyexpensive and complex metal canisters, which can clog in use and are notenvironmentally friendly. Furthermore, misdirecting the spray not onlywastes the product, but can result in irritated eyes, a sticky faceand/or stained clothing.

It has been proposed to use an edible film as a vehicle forunobtrusively delivering breath-freshening agents. See JP 5-236885. ThisJapanese patent application does not, however, teach the inclusion ofantimicrobial agents in the film, using the film to decrease the amountof undesirable bacteria within the oral cavity, or stimulating saliva.Furthermore, this patent application does not disclose employing itsfilm for purposes other than breath freshening or within cavities otherthan the mouth.

U.S. Pat. No. 5,518,902 to Ozaki et al. (Hayashibara) discloses highpullulan content products, such as edible films, dentifrices andpharmaceuticals (column 3, lines 44-56 and Example B-8). The productscan include a variety of ingredients in addition to pullulan, such asother polysaccharides, polyhydric alcohols, antiseptics andflavor-imparting agents (column 4, line 58 to column 5, line 11). Noneof the essential oils, such as thymol, eucalyptol, methyl salicylate ormenthol, are mentioned as suitable ingredients.

U.S. Pat. No. 5,411,945 to Ozaki et al. (Hayashibara) discloses apullulan binder and products produced therewith, including edible films(Example B-2). The products can include a variety of ingredients inaddition to pullulan, such as other polysaccharides, antibacterialagents, flavor-imparting agents and pharmaceutically active substances(column 4, lines 5-15). None of the essential oils are mentioned assuitable ingredients.

U.S. Pat. No. 4,851,394 to Kubodera discloses glucomannan/polyhydricalcohol edible films, which can comprise pullulan (column 3, line 59 tocolumn 4, line 21). The films are contrasted with existingpullulan-based films, which are said to lack resistance to water (column1, lines 40-44). None of the essential oils are mentioned as suitableingredients.

U.S. Pat. No. 3,784,390 Hijiya et al. discloses pullulan films and theiruse in coating and packing materials for foods, pharmaceuticals andother oxygen sensitive materials. All of the examples in this patentteach mixing pullulan in hot water.

U.S. Pat. No. 4,623,394 Nakamura et al. discloses a graduallydisintegrable molded article that can be a film made with pullulan. Thearticles contain a particular heteromannan, which can be locust beangum.

U.S. Pat. No. 4,562,020 Hijiya et al. discloses a process for producinga self-supporting film of a glucan, which can be pullulan.

Japanese Patent Document JP5-1198 discloses films made of polyvinylalcohol and at least one of carrageenan, water-soluble cellulosealpha-starch and water-soluble polysaccharides.

WO 99/17753 discloses rapidly dissolving films for delivery of drugs tobe adsorbed in the digestive tract.

WO 98/26780 discloses a flat, foil, paper or wafer type presentation forthe application and release of active substances in the buccal cavity.The specific active ingredient disclosed in WO 98/26780 isbuprenorphine.

WO 98/20862 discloses a film for use in the oral cavity that can containa cosmetic or pharmaceutical active substance.

WO 98/26763 discloses a flat, foil, paper or wafer like presentation forrelease of active substances into the buccal cavity. The particularactive disclosed is apomorphine.

Despite the existence of rapidly dissolving orally consumable films inthe prior art, there is still room for improvement in such films, and inprocesses for making them.

All references cited herein are incorporated herein by reference intheir entireties.

SUMMARY OF THE INVENTION

The invention provides a physiologically acceptable film, which isparticularly well adapted to adhere to and rapidly dissolve in the mouthof a consumer. In a first embodiment of the invention, the film deliversat least one oral care agent, such as antimicrobial agents and salivarystimulants. The antimicrobial agents are effective against germs thatcause halitosis, dental plaque, and gingivitis. The salivary stimulantsare effective against the condition known as xerostomia or dry mouth.Additionally, the oral care films are a breath freshener effectiveagainst oral malodor. The film former used to make the films accordingto the present invention entraps the oral care agents in the oral cavityto provide extended efficacy.

In a second embodiment of the invention, the rapidly dissolvable filmacts as a vehicle for administering a pharmaceutically active agentorally, through a mucous membrane or an open wound of a patient.

The invention is also directed to a method for producing a supple,non-self-adhering film especially suitable for oral delivery. The methodcomprises mixing a film forming agent and at least one stabilizing agentto provide a film-forming mixture; dissolving water-soluble ingredientsin water to provide an aqueous solution; combining the film-formingmixture and the aqueous solution to provide a hydrated polymer gel;mixing oils to form an oil mixture; adding the oil mixture to thehydrated polymer gel and mixing to provide a uniform emulsified gel;casting the uniform gel on a substrate; and drying the cast gel toprovide a film.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of an agar plate spread with Streptococcusmutans, ATCC 25175, and exposed to a film according to the presentinvention that contains 0.391 mg of essential oils.

FIG. 2 is a photograph of an agar plate spread with Streptococcusmutans, ATCC 25175, and exposed to drops of an essential oil mixturecontaining 0.391 mg of essential oils per drop.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Description of Oral Care Film Compositions

The first embodiment of the invention is a physiologically acceptablefilm that is particularly well adapted to adhere to and dissolve in amouth of a consumer to deliver an antimicrobial agent that kills germsthat cause halitosis, dental plaque and gingivitis. Thus, the film canbe an effective tool in the prevention and treatment of halitosis,dental plaque accumulation, dental tartar accumulation and gingivitis.This film preferably comprises pullulan, thymol, methyl salicylate,eucalyptol and menthol.

LISTERINE® brand mouthwash is, perhaps, the most well-known example ofan antiseptic oral composition that has proven effective in killingmicrobes in the oral cavity that are responsible for plaque, gingivitisand bad breath. LISTERINE® brand mouthwash achieves its antimicrobialeffect through a combination of essential oils that penetrate and killthe microorganisms. These essential oils include precisely balancedamounts of thymol, methyl salicylate, menthol and eucalyptol(hereinafter “the essential oils”) in a hydro alcoholic solution. Manybad breath bacteria live in pits or fissure on the surface of thetongue. Listerine® Antiseptic mouthwash reduces bad breath because ofhigh concentrations of antimicrobial agents in a liquid medium that caneasily penetrate into these pits and fissures. This would not bepossible with a solid dosage form containing low amounts of theseantimicrobial ingredients. However, the preferred consumable film of theinvention captures a significant portion of the hygienic benefits andthe consumer appeal of LISTERINE® brand mouthwash, in a more portableand unobtrusively consumed form.

It was a significant challenge to maintain, the essential oilinteraction and relatively high oil content of LISTERINE® brandmouthwash in a film. However, the inventors have overcome this challengein providing the film of the invention.

A further aspect of this invention is that while the amounts ofLISTERINE® essential oils are relatively high for incorporation in afilm, the film according to the present invention still delivers a lowertotal amount of essential oils per unit dose when compared to that ofLISTERINE® mouthwash. Yet the film suprisingly provides antimicrobialefficacy in the oral cavity. The inventors theorize that the preferredfilm forming ingredient, pullulan, forms a thin layer on the oralsurfaces entrapping the small amount of essential oils which are capableof penetrating into the pits and fissures of the oral cavity to providesustained antimicrobial efficacy.

Although the inventors are presently unaware of any otherbreath-freshening consumable film that provides antimicrobial efficacy,they are aware of a consumable film disclosed in JP 5-236885, which issaid to possess breath-freshening activity, but is not described aspossessing any ingredients having significant antimicrobial activity.Moreover, JP 5-236885 teaches that its film should contain flavor andextract in amounts of 5 to 7 wt %, with the flavor being added as an oil(the essential oils are not disclosed), whereas the film of theinvention preferably has an oil content of at least about 10 wt %, morepreferably about 15 wt % to about 30 wt %, most preferably about 15 wt %to about 25 wt %. Except as otherwise noted in the examples, the amountsof oils and other ingredients in the film are wt % after the filmformulation has been dried to create the film.

The amounts of the specific essential oils used in the film compositionscan vary as long as they are in amounts sufficient to provideantimicrobial efficacy. Generally the amount of thymol, methylsalicylate and eucalyptol is from about 0.01 to about 4 wt % of the filmcomposition, preferably about 0.50 to about 3.0 .wt % and even morepreferably from about 0.70 to about 2.0 wt % of the film. Menthol can beadded from about 0.01 to about 15 wt % of the composition, preferablyabout 2.0 to about 10 wt % and even more preferably from about 3 toabout 9 wt % of the film. The amounts added can be readily determined tothose skilled in the art and can exceed these amounts as long as thetotal oil content does not create sticking or other processing problems.In certain embodiments, the essential oils are combined in amountssynergistically effective to kill the plaque-producing germs that causedental plaque, gingivitis and bad breath.

A major difficulty in formulating a film having such a relatively highoil content is that simply increasing the amount of oil in the filmwithout determining the precise proportions of the many otheringredients typically results in a film that is too moist and thereforedifficult to handle or process. The inventors have discovered how toprovide a high oil content film that is moist enough so that it is notbrittle, but is not so moist that it feels undesirably slimy orsignificantly adheres to adjacent films. Thus, a non-self-adhering filmaccording to the invention can be stored in contact with another suchfilm (e.g., in a stack), or can be wound about itself (e.g., around aspool), without having to place a non-stick agent (e.g., a plastic film,paper or other support) between adjacent portions of film.

The film-forming agent used in the films according to the presentinvention can be selected from the group consisting of pullulan,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinylalcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanthgum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl polymer, amylose, highamylose starch, hydroxypropylated high amylose starch, dextrin, pectin,chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soyprotein isolate, whey protein isolate, casein and mixtures thereof. Apreferred film former is pullulan, in amounts ranging from about 0.01 toabout 99 wt %, preferably about 30 to about 80 wt %, more preferablyfrom about 45 to about 70 wt % of the film and even more preferably fromabout 60 to about 65 wt % of the film.

The film of the invention preferably comprises pullulan. as afilm-forning agent and the essential oils as antimicrobial/flavoringagents, and can further comprise water, additional antimicrobial agents,additional film-forming agents, plasticizing agents, additionalflavoring agents, sulfur precipitating agents, saliva stimulatingagents, cooling agents, surfactants, stabilizing agents, emulsifyingagents, thickening agents, binding agents, coloring agents, sweeteners,fragrances, and the like.

Due to the relatively high oil content in the oral care film, it ispreferable to avoid substantial amounts of humectant in the film (andmore preferable to have no humectant in the film), so as to avoidproducing an overly moist, self-adhering film. In particular, it ispreferred to formulate the film with a plasticizing agent other thanglycerin, which is also a humectant, and with a sweetener other thansorbitol, which is a mild humectant.

Sulfur precipitating agents that reduce oral malodor can also be addedto the oral care films according to the present invention. These agentsbind with, and inactivate, the volatile sulfur compounds that cause alarge percentage of oral malodor. Sulfur precipitating agents useful inthe present invention include metal salts such as copper salts and zincsalts. Preferred salts include copper gluconate, zinc citrate and zincgluconate. The amount of sulfur precipitating agent is from about 0.01to about 2 wt %, preferably about 0.15 wt % to about 1.5 wt. %, evenmore preferably about 0.25 wt % to about 1.0 wt. % of the film.

Saliva stimulating agents can also be added to the oral care filmsaccording to the present invention. Useful saliva stimulating agents arethose disclosed in U.S. Pat. No. 4,820,506, which is incorporated byreference herein in its entirety. Saliva stimulating agents include foodacids such as citric, lactic, malic, succinic, ascorbic, adipic, fumaricand tartaric acids. Preferred food acids are citric, malic and ascorbicacids. The amount of saliva stimulating agents in the film is from about0.01 to about 12 wt %, preferably about 1 wt % to about 10 wt %, evenmore preferably about 2.5 wt % to about 6 wt %.

Preferred plasticizing agents include triacetin in amounts ranging fromabout 0 to about 20 wt %, preferably about 0 to about 2 wt %. Othersuitable plasticizing agents include monoacetin and diacetin.

Preferred cooling agents include monomenthyl succinate, in amountsranging from about 0.001 to about 2.0 wt %, preferably about 0.2 toabout 0.4 wt %. A monomenthyl succinate containing cooling agent isavailable from Mane, Inc. Other suitable cooling agents include WS3,WS23, Ultracool II and the like.

Preferred surfactants include mono and diglycerides of fatty acids andpolyoxyethylene sorbitol esters, such as, Atmos 300 and Polysorbate 80.The surfactant can be added in amounts ranging from about 0.5 to about15 wt %, preferably about 1 to about 5 wt % of the film. Other suitablesurfactants include pluronic acid, sodium lauryl sulfate, and the like.

Preferred stabilizing agents include xanthan gum, locust bean gum andcarrageenan, in amounts ranging from about 0 to about 10 wt %,preferably about 0.1 to about 2 wt % of the film. Other suitablestabilizing agents include guar gum and the like.

Preferred emulsifying agents include triethanolamine stearate,quaternary ammonium compounds, acacia, gelatin, lecithin, bentonite,veegum, and the like, in amounts ranging from about 0 to about 5 wt %,preferably about 0.01 to about 0.7 wt % of the film.

Preferred thickening agents include methylcellulose, carboxylmethylcellulose, and the like, in amounts ranging from about 0 to about20 wt %, preferably about 0.01 to about 5 wt %.

Preferred binding agents include starch, in amounts ranging from about 0to about 10 wt %, preferably about 0.01 to about 2 wt % of the film.

Suitable sweeteners that can. be included are those well known in theart, including both natural and artificial sweeteners. Suitablesweeteners include, e.g.:

-   -   A. water-soluble sweetening agents such as monosaccharides,        disaccharides and polysaccharides such as xylose, ribose,        glucose (dextrose), mannose, galactose, fructose (levulose),        sucrose (sugar), maltose, invert sugar (a mixture of fructose        and glucose derived from sucrose), partially hydrolyzed starch,        corn syrup solids, dihydrochalcones, monellin, steviosides, and        glycyrrhizin;    -   B. water-soluble artificial sweeteners such as the soluble        saccharin salts, i.e., sodium or calcium saccharin salts,        cyclamate salts, the sodium, ammonium or calcium salt of        3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide, the        potassium salt of        3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide        (acesulfame-K), the free acid form of saccharin, and the like;    -   C. dipeptide based sweeteners, such as L-aspartic acid derived        sweeteners, such as L-aspartyl-L-phenylalanine methyl ester        (aspartame) and materials described in U.S. Pat. No. 3,492,131,-        L-alpha-aspartyl-N-(2,2,4,4--tetramethyl-3-thietanyl)-D-alaninamide        hydrate, methyl esters of L-aspartyl-L-phenylglycerin and        L-aspartyl-L-2,5,dihydrophenyl-glycine,        L-aspartyl-2,5-dihydro-L-phenylalanine,        L-aspartyl-L-(1-cyclohexyen)-alanine, and the like;    -   D. water-soluble sweeteners derived from naturally occurring        water-soluble sweeteners, such as a chlorinated derivative of        ordinary sugar (sucrose), known, for example, under the product        description of sucralose; and    -   E. protein based sweeteners such as thaumatoccous danielli        (Thaumatin I and II).

In general, an effective amount of auxiliary sweetener is utilized toprovide the level of sweetness desired for a particular composition, andthis amount will vary with the sweetener selected. This amount willnormally be 0.01% to about 10% by weight of the composition when usingan easily extractable sweetener. The water-soluble sweeteners describedin category A above, are usually used in amounts of about 0.01 to about10 wt %, and preferably in amounts of about 2 to about 5 wt %. Some ofthe sweeteners in category A (e.g., glycyrrhizin) can be used in amountsset forth for categories B-E below due to the sweeteners' knownsweetening ability. In contrast, the sweeteners described in categoriesB-E are generally used in amounts of about 0.01 to about 10 wt %, withabout 2 to about 8 wt % being preferred and about 3 to about 6 wt %being most preferred. These amounts may be used to achieve a desiredlevel of sweetness independent from the flavor level achieved from anyoptional flavor oils used. Of course, sweeteners need not be added tofilms intended for non-oral administration.

The flavorings that can be used include those known to the skilledartisan, such as natural and artificial flavors. These flavorings may bechosen from synthetic flavor oils and flavoring aromatics, and/or oils,oleo resins and extracts derived from plants, leaves, flowers, fruitsand so forth, and combinations thereof. Representative flavor oilsinclude: spearmint oil, cinnamon oil, peppermint oil, clove oil, bayoil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil ofbitter almonds. Also useful are artificial, natural or synthetic fruitflavors such as vanilla, chocolate, coffee, cocoa and citrus oil,including lemon, orange, grape, lime and grapefruit and fruit essencesincluding apple, pear, peach, strawberry, raspberry, cherry, plum,pineapple, apricot and so forth. These flavorings can be usedindividually or in admixture. Commonly used flavors include mints suchas peppermint, artificial vanilla, cinnamon derivatives, and variousfruit flavors, whether employed individually or in admixture. Flavoringssuch as aldehydes and esters including cinnamyl acetate, cinnamaldehyde,citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate,p-methylanisole, and so forth may also be used. Generally, any flavoringor food additive, such as those described in Chemicals Used in FoodProcessing, publication 1274 by the National Academy of Sciences, pages63-258, may be used. Further examples of aldehyde flavorings include,but are not limited to acetaldehyde (apple); benzaldehyde (cherry,almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral(lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange,lemon); ethyl vanillin (vanilla, cream); heliotropine, i.e., piperonal(vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde(spicy fruity flavors); butyraldehyde (butter, cheese); valeraldehyde(butter, cheese); citronellal (modifies, many types); decanal (citrusfruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits);aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits);hexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond);veratraldehyde (vanilla); 2,6-dimethyl- 5-heptenal, i.e. melonal(melon); 2-6-dimethyloctanal (green fruit); and 2-dodecenal (citrus,mandarin); cherry; grape; mixtures thereof; and the like.

The amount of flavoring employed is normally a matter of preferencesubject to such factors as flavor type, individual flavor, and strengthdesired. Thus, the amount may be varied in order to obtain the resultdesired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. In general, amounts of about 0.1 to about 30 wt % areuseable with amounts of about 2 to about 25 wt % being preferred andamounts from about 8 to about 10 wt % are more preferred.

The compositions of this invention can also contain coloring agents orcolorants. The coloring agents are used in amounts effective to producethe desired color. The coloring agents useful in the present invention,include pigments such as titanium dioxide, which may be incorporated inamounts of up to about 5 wt %, and preferably less than about 1 wt %.Colorants can also include natural food colors and dyes suitable forfood, drug and cosmetic applications. These colorants are known as FD&Cdyes and lakes. The materials acceptable for the foregoing spectrum ofuse are preferably water-soluble, and include FD&C Blue No. 2, which isthe disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dyeknown as Green No. 3 comprises a triphenylmethane dye and is themonosodium salt of4-[4-N-ethyl-p-sulfobenzylamino)diphenyl-methylene]-[1-N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclo-hexadienimine]. A full recitation of all FD&C and D&Cdyes and their corresponding chemical structures may be found in theKirk-Othmer Encyclopedia of Chemical Technology, Volume 5, Pages857-884, which text is accordingly incorporated herein by reference.

Antimicrobial Efficacy of Oral Care Films

The preferred embodiment of the oral care film composition according tothe present invention contains the essential oils used in Listerine®mouthwash to provide antimicrobial efficacy. The films are shaped andsized to be placed in the oral cavity. The film adheres to a surface inthe mouth, usually the roof of the mouth or the tongue, and quicklydissolves. The amount of essential oils in one individual film that is apreferred size for placing in the mouth is significantly lower than thatin the recommended amount, 20 ml, of Listerine® mouthwash.

In a preferred formula according to the present invention, the amount ofthymol and eucalyptol in the film is about 70 times less than in themouthwash. The amount of methyl salicylate in the film is about 46 timesless than in the mouthwash. The amount of menthol in the film is about2.8 times less than in the mouthwash. These figures are based oncomparing a 20 ml dose of liquid mouthwash with a 0.0358 gram film.

The inventors have unexpectedly found that the film provides sustainedantimicrobial efficacy at these low amounts of oils. The inventorsbelieve that the efficacy of the essential oils is enhanced by thecreation of a layer of pullulan in the oral cavity that holds theessential oils. This is unexpected because pullulan is water-soluble andthe film dissolves very quickly.

The extended antimicrobial activity is shown in the followingexperiments.

The purpose of these experiments was to determine the antibacterialefficacy of an application of a breath film on tongue malodormicroorganisms thirty, sixty or ninety minutes after use. The thirtyminute study also tested the efficacy of using two films. Subjects'baseline oral malodor microbial recoverable counts were determined byplating the microorganisms recovered from a tongue swab on a selectiveagar medium. The test product was dispensed and subjects dissolved oneor two breath films on their tongue. Subjects remained on the premisesand returned for a second tongue swab thirty, sixty or ninety minutesafter placement of the test product on their tongue. After a forty-eighthour washout period, subjects returned for a no treatment control.

The thirty minute single film use group showed a reduction in mean logmalodor microbial counts compared to the control group. The data wasborderline statistically significant (p=0.052). The difference betweenthe one film group and the no treatment control group represented a42.7% reduction in malodor microbial colony counts.

Statistically significant malodor microbial reduction was also observedwith the two film use group. A 79.6% reduction in malodor microbialcolony counts was obtained (p<0.001).

Statistically significant malodor microbial reduction was observed sixtyminutes after use of a single breath film. A 69.8% reduction in malodormicrobial colony counts was obtained (p=0.002).

Significant malodor reduction was also observed ninety minutes after useof a single breath film. A 69.1% reduction in malodor microbial colonycounts was obtained (p=0.006).

The data from these studies support the following conclusions: (1)Pullulan polymer-based breath film containing essential oils is aneffective antibacterial composition against oral malodor causingbacteria and (2) significant in vivo bacterial reductions were achievedat thirty, sixty and ninety minutes post use.

Experimental Procedures

The procedures used in these antimicrobial studies were as follows. Thesubject were required to refrain from all oral hygiene procedures (e.g.,toothbrushing, oral lavage) eating or drinking any food, beverage orconfectionery products from midnight prior to the study and until thestudy was completed on each test day. Subjects refrained from smoking onmornings prior to the odor evaluations.

In vivo Germ Kill Assay

1. Materials

Test tubes containing 10 ml of sterile 0.01% peptone

Sterile Swabs

OOPS III Agar (B.-F. Turng, G. E. Minah, and W. A. Falkler. Developmentof an Agar Medium for Detection of Oral H₂S-producing Organisms. J DentRes 76 IADR Abstracts 1997.):

Columbia Agar Base (Catalogue # DF0792-17-3) 44 grams Distilled Water 1liter Lead Acetate^(a) (Sigma L3396) 0.2 grams Hemin Solution^(b) (SigmaH-1652) 2 ml Glutathione^(c) (Sigma G4251) 1.2 grams Forty-four grams ofColumbia Blood Agar Base was suspended in 1 liter distilled water andboiled to dissolve completely. The media was sterilized at 121-124° C.15 minutes. ^(a)Dissolved 0.2 grams of lead acetate in 1 ml of distilledH₂O and filter sterilized. Added after autoclaving the base media.^(b)Dissolved 50 mg of hemin in 1 ml of 1N NaOH; qs‘d to 100 ml withdistilled H₂O. Filter sterilized. Added 2 ml per liter of OOPS III afterautoclaving base media. ^(c)Dissolved 1.2 grams of glutathione in 10 mlof distilled H₂O. Filter sterilized. Added after autoclaving base media.

2. Procedure

-   -   a. All media were prereduced in an anaerobic chamber overnight.        Plates were loosely wrapped in plastic bags to prevent excessive        drying.    -   b. Panelists refrained from oral hygiene, eating and drinking        from midnight prior to the assay and until the assay was        complete. Twelve panelists were used for the sixty and ninety        minute experiments. Eighteen panelists were used for the thirty        minute experiments.    -   c. Each panelist swabbed the right side of his tongue by placing        the swab at the midpoint of the tongue and swiping forward to        the tip. The swab was placed in a tube of peptone.    -   d. The panelist received a film treatment, either a single or        double film. Panelists placed the breath film on the left side        of their tongue covering the tongue from the midpoint to the tip        and allowed the film to dissolve with the mouth slightly open        for thirty seconds to prevent the film from sticking to the        palate.    -   e. After thirty or sixty minutes, panelists swabbed the left        side of the tongue by placing the swab at the midpoint of the        tongue and swiping forward to the tip. The swab was placed in a        tube of peptone.    -   f. The tubes of peptone were vortexed vigorously for 10 seconds,        and serial dilutions were made. The 10⁻⁴ dilution was plated in        duplicate on OOPS III Agar using a Spiral Biotech        Autoplate 4000. (Bethesda, Md.). All plates were identified with        the subject's initials, assay date, sampling time station, and        replicate number.    -   g. The plates were incubated in an anaerobic chamber at        35-37° C. for 7 days to permit full development of colonies        without overgrowth.    -   h. After a 48 hour wash out period, panelists returned for the        no treatment control. No film was applied, and steps (e)        through (g) were followed as described above.    -   i. After a 48 hour wash out period, the sixty minute panelists        returned for another single film application. Steps (a)        through (h) were followed, with the exception that panelists        returned after 90 min in step e.    -   j. The dark-pigmented colonies (H₂S-producing organisms) were        counted as whole plate counts by hand under appropriate        magnification or by Segment counts using a Spiral Biotech        counting template. The appropriate code was entered on the data        sheet to permit interpretation of the counts. The CFU's counted        were converted to CFU/ml by dividing by the appropriate        exponential volume constant listed in Table A and multiplying        by 1000. This value was then multiplied by the dilution factor        of the plate (10⁴).

TABLE A Exponential Volume Constants for Segment Pairs Last CountedSegment Exponential Volume Constant  8 1.214  9 2.968 10 5.500 11 9.15712 14.482 13 25.015 Total Plate 50.030

The film used in the in vivo germ kill tests was Example 19 as describedin Table 2. The films used in the study were approximately 22 mm×32 mm,between about 0.0013 and 0.0015 inches thick and weighed between about35 to about 37 mg.

The enhanced activity of the essential oil containing pullulan film isalso shown in FIGS. 1 and 2. FIG. 1 is a photograph of an agar platespread with Streptococcus mutans, ATCC # 25175, to which a piece of anessential oil pullulan film according to the present invention wasadded. The piece of film delivered approximately 0.391 mg of essentialoils using Example 15 listed below.

FIG. 2 is a photograph of an agar plate spread with Streptococcusmutans, ATCC # 25175 to which drops of essential oils have been added.The drops were 148 ul in volume and contained 0.391 mg of essentialoils. The percentages of each essential oil in the drop are 2.200%menthol, 0.186% eucalyptol, 0.186% methyl salicylate and 0.1300% thymolin a hydro alcohol solution.

The area or zone of inhibition around the film in FIG. 1 is much largerthan the dimensions of the film. This is due to the presence of pullulanbecause the oils in the pullulan film were spread by the pullulan,diffused outward and did not wash away after repeated rinses. Incontrast, the essential oils in FIG. 2 did not diffuse away from thedroplet, remained as a circle and easily washed off after 1-2 rinses.This shows that the antimicrobial efficacy of the essential oils isenhanced by the presence of pullulan.

Methods for Preparing Essential Oil Containing Films

Methods for preparing films according to the invention are capable ofencapsulating the oil ingredients within the film-forming matrix andmaintaining the integrity of the film, even when the film contains oilsin amounts of 10 wt % or more.

In certain methods for preparing films according to the invention, thefilm-forming ingredients are mixed and hydrated with water separatelyfrom the water-soluble ingredients, which are mixed in aqueous solutionseparately from the organic ingredients and surfactants. In thesemethods, the final formulation is preferably produced by mixing thefilm-forming phase with the aqueous phase, then mixing in the organicphase, which includes surfactants, such as Polysorbate 80 and Atmos 300.This mass is mixed until emulsified. In other embodiments, the aqueousand film forming phases are combined into a single phase by dissolvingthe water soluble ingredients in the water and then adding the gums tohydrate. The organic phase is then added to this single aqueous phase.

The resulting formulation is cast on a suitable substrate and dried toform a film. The film is preferably air-dried or dried under warm airand cut to a desired dimension, packaged and stored. The film cancontain from about 0.1% to about 10 wt % moisture, preferably from about3 % to about 8 wt % moisture, even more preferably from about 4 to about7 wt % moisture.

The film-fonning phase can include pullulan and stabilizing agents suchas xanthan gum, locust bean gum and carrageenan. These ingredients aremixed and then hydrated in water for about 30 to about 48 hours to forma gel. The water is preferably heated to a temperature of about 25 toabout 45° C. to promote hydration. The amount of water is about 40 to80% of the gel. The resulting hydrated gel is then chilled to atemperature of about 20 to about 30° C. for about 1 to about 48 hours.The water is preferably deionized.

The aqueous phase can include ingredients such as coloring agent(s),copper gluconate and sweetener. The water is preferably deionized andthe amount of water used is about 5 to about 80 wt % of the final gelmixture.

If sodium saccharin and copper gluconate are both ingredients in theformulation, it is preferable to dissolve them separately in solution toavoid precipitation.

In a preferred method of producing essential oil containing filmsaccording to the invention, it is possible to hydrate the film-formingingredients and combine all of the ingredients without heating. Thepreferred method of producing films comprises dissolving thewater-soluble ingredients in water to form an aqueous mixture; mixingthe film-forming ingredients in powder form to form a powder mixture;adding the powder mixture to the aqueous mixture to form a hydratedpolymer gel; stirring the hydrated polymer at room temperature for about30 minutes to about 48 hours; mixing the cooling agent, thymol andmenthol in the flavor oil to form an oil mixture; adding methylsalicylate; eucalyptol and surfactants to the oil mixture; adding theoil mixture to the hydrated polymer gel and mixing until uniform;deaerating the film until air bubbles are removed, casting the uniformmixture on a suitable substrate; and drying the cast mixture to form afilm.

The preferred method for making an essential oil containing filmhydrates the film-forming ingredients without heating the water. Heatingthe ingredients increases energy costs in the manufacturing process.Moreover, heating results in undesirable losses of volatile ingredientsto evaporation, which also affects the germ killing activity of thecomposition due to the loss of essential oils. Further, mixing the oilsin two steps minimizes the amount of flavor lost.

While not wishing to be bound by any theories, it is believed that thefilm-forming ingredients can be hydrated and mixed without heating dueto an ionic effect known as the Donnan equilibrium. Hydrating thefilm-forming agents in the presence of electrolytes in solutioneffectively lowers the viscosity of the polymer gel being formed, thusincreasing the efficiency of the hydrating process. The water-solubleingredients of the formulation provide the electrolytes, which aredissolved in the hydration solution prior to addition of thefilm-forming ingredients. High-shear mixing also accelerates hydration,which delumps the powders, providing greater surface area for watercontact. In addition, local heating effects, generated in the shearregions, provide energy for hydration without substantially raising thetemperature of the mass.

It is preferable to avoid adding both copper gluconate and saccharin atthe same time to the aqueous solution, as a precipitate will form. Thus,it is preferred to combine sweeteners other than saccharin with coppergluconate.

Description of Film Compositions that Deliver Pharmaceutical Agents

A second embodiment of the invention is a fast dissolving film thatincludes at least one physiologically acceptable, pharmaceuticallyactive agent. The expression “physiologically acceptable” as used hereinis intended to encompass compounds, which upon administration to apatient, are adequately tolerated without causing undue negative sideeffects. The expression encompasses edible compounds.

The expression “pharmaceutically active agents” as used herein isintended to encompass agents other than foods, which promote astructural and/or functional change in and/or on bodies to which theyhave been administered. These agents are not particularly limited;however, they should be physiologically acceptable and compatible withthe film. Suitable pharmaceutically active agents include; but are notlimited to:

-   -   A. antimicrobial agents, such as triclosan, cetyl pyridium        chloride, domiphen bromide, quaternary ammonium salts, zinc        compounds, sanguinarine, fluorides, alexidine, octonidine, EDTA,        and the like,    -   B. non-steroidal anti-inflammatory drugs, such as aspirin,        acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen        calcium, naproxen, tolmetin sodium, indomethacin, and the like,    -   C. anti-tussives, such as benzonatate, caramiphen edisylate,        menthol, dextromethorphan hydrobromide, chlophedianol        hydrochloride, and the like,    -   D. decongestants, such as pseudoephedrine hydrochloride,        phenylepherine, phenylpropanolamine, pseudoephedrine sulfate,        and the like,    -   E. anti-histamines, such as brompheniramine maleate,        chlorpheniramine maleate, carbinoxamine maleate, clemastine        fumarate, dexchlorpheniramine maleate, diphenhydramine        hydrochloride, diphenylpyraline hydrochloride, azatadine        meleate, diphenhydramine citrate, doxylamine succinate,        promethazine hydrochloride, pyrilamine maleate, tripelennamine        citrate, triprolidine hydrochloride, acrivastine, loratadine,        brompheniramine, dexbrompheniramine, and the like,    -   F. expectorants, such as guaifenesin, ipecac, potassium iodide,        terpin hydrate, and the like,    -   G. anti-diarrheals, such a loperamide, and the like,    -   H. H₂-antagonists, such as famotidine, ranitidine, and the like;        and    -   I. proton pump inhibitors, such as omeprazole, lansoprazole, and        the like,    -   J. general nonselective CNS depressants, such as aliphatic        alcohols, barbiturates and the like,    -   K. general nonselective CNS stimulants such as caffeine,        nicotine, strychnine, picrotoxin, pentylenetetrazol and the        like,    -   L. drugs that selectively modify CNS function such as        phenyhydantoin, phenobarbital, primidone, carbamazepine,        ethosuximide, methsuximide, phensuximide, trimethadione,        diazepam, benzodiazepines, phenacemide, pheneturide,        acetazolamide, sulthiame, bromide, and the like,    -   M. antiparkinsonism drugs such as levodopa, amantadine and the        like,    -   N. narcotic-analgesics such as morphine, heroin, hydromorphone,        metopon, oxymorphone, levorphanol, codeine, hydrocodone,        xycodone, nalorphine, naloxone, naltrexone and the like,    -   O. analgesic-antipyretics such as salycilates, phenylbutazone,        indomethacin, phenacetin and the like,    -   P. psychopharmacological drugs such as chlorpromazine,        methotrimeprazine, haloperidol, clozapine, reserpine,        imipramine, tranylcypromine, phenelzine, lithium and the like.

The amount of medicament that can be used in the rapidly dissolvingfilms, according to the present invention, is dependent upon the doseneeded to provide an effective amount of the medicament. Examples ofdoses for specific medicaments that can be delivered per one strip ofrapidly dissolving oral film are reviewed in Table 1.

TABLE 1 MEDICAMENT DOSE Chlorpheniramine Maleate 4 mg. BrompheniramineMaleate 4 mg. Dexchlorpheniramine 2 mg. Dexbrompheniramine 2 mg.Triprolidine Hydrochloride 2.5 mg. Acrivastine 8 mg. Azatadine Maleate 1mg. Loratidine 10 mg. Phenylephrine Hydrochloride 10 mg.Dextromethorphan Hydrochloride 10–20 mg. Ketoprofen 12.5 mg. SumatriptanSuccinate 35–70 mg. Zolmitriptan 2.5 mg. Loperamide 2 mg. Famotidine 10mg. Nicotine 2 mg. Diphenhydramine Hydrochloride 25 mg. PseudoephedrineHydrochloride 30 mg.

The ingredients used to make the pharmaceutical containing films aresimilar to those used to make oral care films. Specifically, theplasticizing agents, cooling agents, surfactants, stabilizing agents,emulsifiers, thickening agents, binding agents, film formers,sweeteners, flavors and colors described above can-also be used in allof the films according to the present invention.

The films that deliver a pharmaceutical agent can also include atriglyceride. Examples of triglycerides include vegetable oils such ascorn oil, sunflower oil, peanut oil, olive oil, canola oil, soybean oiland mixtures thereof. A preferred triglyceride is olive oil. Thetriglyceride is added to the film in amounts from about 0.1 wt % toabout 12 wt %, preferably in a range from about 0.5 wt % to about 9 wt%, of the film.

The films that contain pharmaceutical agents also can include apreservative. The preservative is added in amounts. from about 0.001 wt% to about 5 wt %, preferably from about 0.01 wt % to about 1 wt. % ofthe film. Preferred preservatives include sodium benzoate and potassiumsorbate.

The pharmaceutical agent containing films can also include apolyethylene oxide compound. The molecular weight of the polyethyleneoxide compound ranges from about 50,000 to about 6,000,000. A preferredpolyethylene oxide compound is N-10 available from Union CarbideCorporation. The polyethylene oxide compound is added in amounts fromabout 0.1 wt % to about 5 wt %, preferably from about 0.2 wt % to about4.0 wt % of the film.

The pharmaceutical agent containing films can also include propyleneglycol. The propylene glycol is added in amounts from about 1 wt % toabout 20 wt %, preferably from about 5 wt % to about 15 wt % of thefilm.

The active ingredient used in the film can be coated to mask the tasteof the active ingredient or to prevent the active ingredient from thenumbing the tongue or other surfaces in the oral cavity. The coatingsthat can be used are known to those skilled in the art. These includepolymers such, as Eudragit® E, cellulosics, such as ethylcellulose, andthe like.

An additional way to mask the taste of the active ingredient is by usingan ion exchange resin such as Amberlite RP-69, available from Rohm andHaas, and Dow XYS-40010.00, available from the Dow Chemcial Co.

EXAMPLES

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

Preparation Method I

The following method was used to prepare the films of Examples 1-13.

A. The film-forming ingredients (e.g., xanthan gum, locust bean gum,carrageenan and pullulan) other than Polysorbate 80 and Atmos 300 aremixed and hydrated in hot purified water to form a gel and stored in arefrigerator overnight at a temperature of approximately 4° C. to formpreparation A.

B. The coloring agent(s), copper gluconate and sweetener are added toand dissolved in purified water to form preparation B.

C. Preparation B is added to preparation A and mixed well to formpreparation C.

D. The flavoring agent and the oils (e.g., cooling agent, thymol, methylsalicylate, eucalyptol and menthol) are mixed to form preparation D.

E. The polysorbate 80 and Atmos 300 are added to preparation D and mixedwell to form preparation E.

F. Preparation E is added to preparation C and mixed well to formpreparation F.

Preparation F is poured on a mold and cast to form a film of a desiredthickness at room temperature. The film is dried under warm air and cutto a desired dimension, packaged and stored.

Preparation Method II

Examples 14-18 were prepared using a preferred method, which comprisedthe following steps:

-   -   A. dissolve copper gluconate, acesulfame K, aspartame, glycerin,        sorbitol and dye in purified water to form an aqueous mixture;    -   B. mix pullulan, xanthan gum, locust bean gum and carrageenan        together in powder form to form a powder mixture;    -   C. add the powder mixture from step B to the aqueous mixture        from step A to form a hydrated polymer gel;    -   D. stir the hydrated polymer from step C at slow speed (about        50-100 RPM) overnight at room temperature;    -   E. mix and dissolve cooling agent, thymol and menthol in the        flavor oil;    -   F. add methyl salicylate, eucalyptol, Polysorbate 80 and Atmos        300 to the oil mixture from step E;    -   G. add the oil mixture from step F to the hydrated polymer gel        from step D and mix until uniform;    -   H. cast the uniform mixture from step G on a suitable backing;        and    -   I. dry the cast mixture to form a film.

Example 1

Example 1 produced a film according to the invention having a blue-greentint, a mint odor and a refreshing mint taste.

Examples 2-4

Examples 2-4 contain sorbitol, glycerin or both. These examples yieldedproducts that easily broke off pieces, or were too moist and/orself-adhering. However they did produce films that rapidly dissolved inthe oral cavity with a refreshing mint taste.

Examples 5-6

Examples 5 and 6 removed glycerin and sorbitol. The resultant films didnot stick together during processing and packaging and were moremoisture stable over a long time frame.

Examples 7-9

Examples 7-9 were produced to determine the effect of Avicel® on germkilling activity. While Examples 7-9 produced more acceptable films froma processing and handling perspective, they had diminished antimicrobialactivity relative to films without Avicel®, such as Example 8.

Examples 10-15

Examples 10-15 varied the amounts of aspartame and menthol to alter thesweetness and coolness of the film.

Example 16

Example 16 was prepared by replacing the sorbitol replaced withmaltitol, which has less humectant properties. The resultant film wasless sticky during processing and long term storage.

Example 17

Example 17 is prepared in which pullulan is replaced with another filmformer, polyvinyl pyrrolidone, to produce films according to theinvention.

Example 18

Example 18 is prepared in which pullulan is partially replaced withanother film former, konjac gum, to produce films according to theinvention.

Example 19

Example 19 represents a film containing a salivary stimulant, citricacid.

Example 20

Example 20 is the film composition used in the antimicrobial efficacystudies described above.

The formulas for examples 1-20 are summarized in Table 2. The amounts inthese examples are presented as the actual weight (grams) or w/w %.These formulas create the solution/gel that is cast and dried into afilm. The actual amount of each ingredient in the finished, dried filmdepends upon the amount of relative moisture removed during drying.

TABLE 2 Ex. 1 2 3 4 5 6 7 8 9 Ingredient w/w % wt (g) wt (g) wt (g) wt(g) wt (g) wt (g) wt (g) wt (g) Xanthan Gum, Food Grade 0.1070 11.6012.60 11.60 Xanthan Gum (1% solution) 3.85 3.85 3.85 3.85 3.85 LocustBean Gum, Clarified 0.2150 23.40 25.40 23.40 Locust Bean Gum (1% 7.707.70 7.70 7.70 7.70 solution) Polyvinyl Pyrrolidone Konjac GumCarrageenan 1.0730 116.60 126.10 116.60 Carrageenan (5% solution) 7.707.70 7.70 7.70 7.70 Avicel 500.00 500.00 Pullulan 51.5780 5604.006513.00 5949.00 Pullulan (25% sol) 74 74 74 74 74 Thymol NF 0.4070 0.1460.146 0.146 40.70 40.70 40.70 Methyl Salicylate NF 0.4210 0.151 0.1510.151 58.50 58.50 58.50 Eucalyptol 0.5850 0.21 0.21 0.21 42.10 42.1042.10 Menthol USP 5.8830 2.23 2.11 2.11 588.00 588.00 588.00 Mint flavor8.3640 2 3.0 3.0 836.00 836.00 836.00 Citric Acid Copper gluconate1.1150 0.275 0.41 0.14 112.00 112.00 112.00 Purified water, USP/EP 22.322 10.22 12.22 8.0 8.0 2230.00 2230.00 2230.00 Sod. saccharin USPgranulate 6.6910 1.8 1.4 1.4 2.0 2.4 Sodium saccharin 609.00 609.00609.00 Acesulfame-K Aspartame Cooling agent 0.05 0.05 0.05 13.90 13.9013.90 Maltitol Sorbitol (crystalline) 64.30 64.30 64.30 Sorbitol 70%sol. 4 4.0 Glycerin 2 2.0 136.00 136.00 136.00 Polysorbate 80 NF/EP0.5580 0.3 0.2 0.2 0.2 0.2 112.00 112.00 112.00 Atmos 300 0.5580 112.00112.00 112.00 Atlas 3000 0.3 0.2 0.2 0.2 0.2 Hi Set C Starch 77.0 FD & CGreen # 3 0.0084 0.3 0.3 0.3 0.3 0.3 0.84 0.84 0.84 D & C Yellow #10 1011 12 13 14 15 16 17 18 19 20 Ingredient wt (g) wt (g) wt (g) wt (g) w/w% w/w % w/w % w/w % w/w % w/w % w/w % Xanthan Gum, Food Grade 0.03850.0385 0.0385 0.0385 0.0342 0.0342 0.0342 0.04 0.04 0.34 0.0342 XanthanGum (1% solution) Locust Bean Gum, Clarified 0.077 0.077 0.077 0.0770.0684 0.0684 0.0684 0.07 0.07 0.68 0.0684 Locust Bean Gum (1% solution)Polyvinyl Pyrrolidone 16.5 Konjac Gum 5.0 Carrageenan 0.385 0.385 0.3850.385 0.342 0.342 0.342 0.34 0.34 .34 0.342 Carrageenan (5% solution)Avicel Pullulan 18.5 18.5 18.5 18.5 16.43 16.43 16.43 11.0 16.34 16.43Pullulan (25% sol) Thymol NF 0.146 0.146 0.146 0.146 0.130 0.13 0.130.13 0.13 0.129 0.13 Methyl Salicylate NF 0.21 0.21 0.21 0.21 0.1860.186 0.186 0.186 0.186 0.185 0.18 Eucalyptol 0.21 0.21 0.21 0.21 0.1860.186 0.186 0.186 0.186 0.185 0.18 Menthol USP 2.11 1.95 2.36 2.36 2.0962.520 2.096 2.096 2.096 2.084 2.096 Mint flavor 3.0 3.0 3.0 3.0 2.6642.344 2.664 2.664 2.664 2.649 2.0 Citric Acid 2.5 Copper gluconate 0.40.4 0.4 0.4 0.355 0.355 0.355 0.35 0.35 0.353 0.355 Purified water,USP/EP 84.25 84.25 84.25 84.25 74.81 74.63 74.81 75 75 74.39 72.2168Sod. saccharin USP granulate Sodium saccharin Acesulfame-K 0.5 0.5 0.50.5 0.444 0.444 0.444 0.45 0.45 .04420 0.444 Aspartame 1.30 1.60 1.301.60 1.421 1.421 1.421 1.4 1.4 1.413 1.421 Cooling agent 0.10 0.10 0.100.10 0.089 0.089 0.089 0.089 0.089 0.088 0.89 Maltitol 2.80 Sorbitol(crystalline) Sorbitol 70% sol. 0.199 Glycerin 0.418 Polysorbate 80NF/EP 0.4 0.4 0.4 0.4 0.355 0.355 0.355 0.355 0.355 0.353 0.355 Atmos300 0.355 .0355 0.355 0.355 0.355 0.353 0.355 Atlas 3000 0.4 0.4 0.4 0.4Hi Set C Starch FD & C Green # 3 0.003 0.003 0.003 0.003 0.0026 0.00260.0026 0.0026 0.0026 D & C Yellow #10

The following examples are films according to the second embodiment ofthe present invention, in which the rapidly dissolving film contains apharmaceutical agent. Examples 21A-21E, listed in Table 3, aremedicament containing rapidly dissolvable oral film formulas. Theamounts in Table 3 are in milligrams.

TABLE 3 Example Number 21A 21B 21C 21D 21E Dextromethorphan HBr 7.500Phenylepherine HCI 10.0000 10.0000 Chlorpheniramine 4.0000 MaleateLoperamide HCI 2.0000 Nicotine 2.0000 Xanthan Gum 0.0818 0.0818 0.08180.0818 0.0818 Locust Bean Gum 0.0954 0.0954 0.0954 0.0954 0.0954Carrageenan 0.4088 0.4088 0.4088 0.4088 0.4088 Pullulan 21.8036 21.803621.8036 21.8036 21.8036 Sodium Benzoate 0.0954 0.0954 0.0954 0.09540.0954 Acesulfame Potassium 0.6814 0.6814 0.6814 0.6814 0.6814 SaltAspartame NF 1.9078 1.9078 1.9078 1.9078 1.9078 Purified Water * * * * *Cooling agent 0.1363 0.1363 0.1363 0.1363 0.1363 Menthol 2.7255 2.72552.7255 2.7255 2.7255 Polysorbate 80 NF 0.4770 0.4770 0.4770 0.47700.4770 Atmos 300 0.4770 0.4770 0.4770 0.4770 0.4770 Propylene Glycol4.0882 4.0882 4.0882 4.0882 4.0882 Olive Oil 0.6814 0.6814 0.6814 0.68140.6814 Titanium Dioxide 0.3407 0.3407 0.3407 0.3407 0.3407 Total DoseWeight 41.5000 44.0000 48.0000 36.0000 36.0000 *Calculated assumingcomplete evaporation of water from the films after drying

Table 4 summarizes additional films according to the present invention.The amounts in Table 4 are % w/w prior to drying.

TABLE 4 Examples 22A 22B 22C 22D 22E 22F 22G 22H 22I Xanthan Gum .03 .03.06 .03 .03 .03 .06 .06 .06 Locust Bean Gum .07 .07 .07 .07 .07 .07 .07.07 .07 Carrageenan 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Pullulan 16.016.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Sodium Benzoate 0.1 0.1 0.1 .07.07 .07 .07 .07 0.7 Acesulfame 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5Potassium Aspartame 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 Water qs100qs100 qs100 Qs100 qs100 qs100 qs100 qs100 Qs100 Cooling agent 0.1 0.10.1 0.1 0.1 0.1 0.1 0.1 0.1 Menthol 2.0 2.0 2.0 1.3 2.0 2.0 2.0 2.0 2.0Polysorbate 80 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Atmos 3000.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Propylene Glycol 1.0 1.01.0 1.0 1.0 1.0 3.0 3.0 3.0 Peg 1450 — 3.10 — — — — — — — Olive Oil — —— 1-2 2.0 2.0 .5-2 — .5 Polyox N-10 — — — — — — — — 1.0 Titanium Dioxide— 0.25 0.25 0.25 0.25 — 0.25 — 0.25

Example 22A was used to make films containing a) 7.5 mg ofdextromethorphan hydrobromide, b) 2.5 mg of tripolidine, c) 4.0 mg ofchlorpheniramine maleate and d) 12.5 mg of diphenhydraminehydrochloride.

Example 22B was used to make a film containing 10 mg of dextrometorphanhydrobromide.

Example 22C was used to make a film containing 10 mg of dextromethorphanhydrobromide.

Example 22D was used to make a film containing a) 10 mg ofphenylepherine hydrochloride, b) 10 mg of phenylepherine hydrochlorideand 4 mg of chlorpheniramine maleate and c) 10 mg of dextromethorphanhydrobromide.

Example 22E was used to make a film containing 7.5 mg dextromethorphanhydrobromide.

Example 22F was used to make a film containing 20 mg of coateddextromethorphan hydrobromide to provide a 7.5 mg dose.

Example 22G was used to make a film containing a) 7.5 mgdextromethorphan hydrobromide, b) 10 mg phenylepherine hydrochloride andc) 10 mg phenylepherine hydrochloride and 4 mg chlorpheniramine maleate.

Example 22H was used to make a film containing 15 mg of dextromethorphanhydrobromide.

Example 22I was used to make a film containing 15 mg of dextromethorphanhydrobromide.

Processes for Making Pharmecutical Containing Films

Example 22A was made using the following procedure.

-   -   1. Add the sodium benzoate and sweeteners to water.    -   2. Mix the locust bean gum, xanthan gum and carrageenan        together.    -   3. Add the gum mixture to the mixture of step 1 and mix until        dissolved.    -   4. Mix the active ingredient with either water or propylene        glycol. Heat if needed.    -   5. Add the remaining ingredients to the mixture of step 4 or mix        the remaining ingredients in a separate mixture.    -   6. Add the mixtures of step 4 and step 5 to the mixture of        step 3. Cast and dry to make a film and cut to a size to achieve        the desired dose.

Examples 22B-22E were made using the following procedure.

-   -   1. Add the sodium benzo ate to water heated to 50 C. Mix to        dissolve.    -   2. Separately, add the Peg 1450, titanium dioxide and active        ingredient to the mixture of step 1, mixing with each addition.    -   3. Mix the locust bean gum, xanthan gum and carrageenan        together.    -   4. Add the gums to the mixture of step 2 and mix until dissolve.    -   5. Add the remaining ingredients together with heat if needed.    -   6. Add the mixture of steps 4 and 5 together. Cast and dry to        make a film and cut to a size to achieve the desired dose.

Examples 22F-22I were made in the same manner as Examples 20B-20E,except the active was dispersed right before the was cast.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

1. A method for preparing a physiologically compatible film, said methodcomprising: mixing at least one water soluble film former and at leastone stabilizing agent selected from the group consisting of xanthan gum,locust bean gum, carrageenan, guar gum and mixtures thereof to provide afilm-forming mixture; providing water soluble ingredients capable offorming electrolytes when dissolved in water; dissolving thewater-soluble ingredients in water to provide an electrolyte containingaqueous solution; combining said film-forming mixture and the aqueoussolution to provide a hydrated polymer gel; mixing oils to form an oilmixture that comprises at least one essential oil selected from thegroup consisting of thymol, methyl salicylate, eucalyptol, and mentholwherein the total amount of the oils in the oil mixture is at leastabout 5 wt % of the total weight of ingredients; adding said oil mixtureto said hydrated polymer gel and mixing to provide a uniform gel;casting the uniform gel on a substrate; and drying the cast gel toprovide said film.
 2. The method according to claim 1, wherein at leastone surfactant is mixed into said oil mixture.
 3. The method accordingto claim 2, wherein said total amount of oils is at least about 15 wt %.4. The method according to claim 1, wherein said drying is conducteduntil said film has a moisture content of about 3 wt % to about 8 wt %.5. The method according to claim 1, wherein, prior to being combinedwith said aqueous solution, said film-forming mixture is hydrated withwater at a temperature of about 25 to about 50° C. and subsequentlychilled to a temperature of about 4 to about 30° C. for about 2 to 48hours.
 6. The method according to claim 1, wherein said film-formingmixture is a powder, which is directly combined with said aqueoussolution.
 7. The method according to claim 6, wherein said hydratedpolymer gel is formed without heating.
 8. The method according to claim7, wherein said hydrated polymer gel is stirred at room temperature forabout 2 to about 48 hours.
 9. The method according to claim 8, whereinsaid oil mixture is prepared by mixing thymol and menthol in a flavoroil, and subsequently adding methyl salicylate and eucalyptol.
 10. Anon-self-adhering film produced according to the method of claim
 1. 11.The method according to claim 1, wherein the water soluble film formeris selected from the group consisting of pullulan, hydroxyproplymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodiumalginate, polyethylene glycol, tragacanth gum, guar gum, acacia gum,arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylpolymer, amylose, high amylose starch, hydroxypropylated high amylosestarch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen,gelatin, zein, gluten, soy protein isolate, whey protein isolate, caseinand mixtures thereof.
 12. The method according to claim 11, wherein saidwater soluble polymer is pullulan.